Certain pyrazole derivatives as corticotropin-releasing factor CRF1 ligands

ABSTRACT

Disclosed are compounds that are highly selective partial agonists or antagonists at human CRF 1  receptors that are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. The compounds have the formula                    
     or the pharmaceutically acceptable salts thereof wherein Ar, R 1 , R 2 , A, and Z are various organic and inorganic substituents.

This is a continuation of application Ser. No. 09/614,582, filed Jul.12, 2000, now U.S. Pat. No. 6,300,360, which is a continuation ofapplication Ser. No. 09/369,100, filed Aug. 5, 1999, now U.S. Pat. No.6,127,399, which is a continuation of application Ser. No. 09/088,149,filed Jun. 1, 1998, now U.S. Pat. No. 5,973,152, which is a continuationof application Ser. No. 08/751,107, filed Nov. 15, 1996, now U.S. Pat.No. 5,760,225.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain pyrazole derivatives which selectivelybind to corticotropin-releasing factor (CRF) receptors. This inventionalso relates to pharmaceutical compositions comprising such compounds.It further relates to the use of such compounds in treating stressrelated disorders such as post traumatic stress disorder (PTSD) as wellas depression, headache and anxiety.

2. Description of the Related Art

A variety of pyrazoles have been described in the prior art.International Patent Application Publication No. WO96/01254 (Jan. 18,1996) discloses certain pyrazole derivatives as herbicides.International Patent Application Publication No. WO94/13643 (Jun. 23,1994 ) discloses certain pyrazoles and pyrazolopyrimidines as CRFantagonists. International Patent Application Publication No. WO94/13644(Jun. 23, 1994) and International Patent Application Publication No.WO94/13661 (Jun. 23, 1994) also disclose certain substituted pyrazoleswhich have CRF antagonistic activities. German Patent DD210265 (Jun. 06,1984) discloses certain pyrazoles as xanthine oxidase inhibitors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withCRF receptors.

The invention provides pharmaceutical compositions comprising compoundsof Formula 1. It further relates to the use of such compounds intreating stress related disorders such as post traumatic stress disorder(PTSD) as well as depression, headache and anxiety. Accordingly, a broadembodiment of the invention is directed to a compound of Formula I:

wherein

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl 4 or 5-pyrimidinyl, mono, disubstituted, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted,

A is CH₂ or C═O;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl;

Z is a group of the formula

where

R₁ is hydrogen, C₁-C₆ alkyl, or (C₁-C₆ )alkyl-W-R₈, where W is O, S NH,or N(C₁-C₆) alkyl, and R is hydrogen or C₁-C₆ alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2; and

E represents CHR₅ where R₅ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, halogen, or trifluoromethyl, phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds;

or

E is a group of the formula

where

R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl,imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two doublebonds; or

Z is —NR₆R₇

where R₆ and R₇ are the same or different and represent

hydrogen, C₁-C₆ alkyl, (C₁-C₆ )alkyl-Y-R₉, wherein Y is O, S NH, N(C₁-C₆alkyl), and R₉ is hydrogen or C₁-C₆ alkyl; or

aryl(C₁-C₆)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5- pyrimidinyl, each of whichis mono or disubstituted with halogen, hydroxy, (C₁-C₆ )alkyl,(C₁-C₆)alkoxy; or

R₆ and R₇ taken together represent —(CH₂)_(n)—Y—(CH₂)_(m)— wherein n is2, or 3, Y is CH₂, O, S or NR_(6,) wherein R₆ is C₁-C₆ alkyl, phenyl,2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, or 2-, 4-, or 5-pyrimidinyl,and m is 1, 2 or 3.

These compounds are highly selective partial agonists or antagonists atCRF receptors and are useful in the diagnosis and treatment of stressrelated disorders such as post traumatic stress disorder (PTSD) as wellas depression and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

In addition to the compounds of Formula I above, the invention providescompounds encompassed by Formula IIA:

wherein

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5- pyrimidinyl, mono, disubstituted, or trisubstitutedwith halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy with the proviso thatat least one of the positions on Ar ortho to the point of attachment tothe pyrazole ring is substituted;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl;

Z is a group of the formula

where

R₄ is hydrogen, C₁-C₆ alkyl, or (C₁-C₆ )alkyl-W-R₈, where W is O, S NH,or N(C₁-C₆) alkyl, and R₈ is hydrogen or C₁-C₆ alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2;and

E represents CHR₅ where R₅ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, halogen, or trifluoromethyl, phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds;

or

E is a group of the formula

where

R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl,imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two doublebonds; or

Z is —NR₆R₇,

where R₆ and R₇ are the same or different and represent

hydrogen, C₁-C₆ alkyl, (C₁-C₆ )alkyl-Y-R₉, wherein Y is O, S NH, N(C₁-C₆alkyl), and R₉ is hydrogen or C₁-C₆ alkyl; or

aryl(C₁-C₆)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or4-pyridinyl, 2- or 3-thienyl or 2-, 4, or 5- pyrimidinyl, each of whichis mono- or disubstituted with halogen, hydroxy, (C₁-C₆ )alkyl, (C₁-C₆)alkoxy; or

R₆ and R₇ taken together represent —(CH₂)_(n)-Y-(CH₂)_(m)— wherein n is2, or 3, Y is CH₂, O, S or NR₆, wherein R₆ is C₁-C₆ alkyl, phenyl, 2-,3-, or 4-pyridinyl, 2- or 3-thienyl, or 2-, 4-, or 5-pyrimidinyl, and mis 1, 2 or 3.

Preferred compounds of formula IIA are those where Z is1,2,3,4-tetrahydroisoquinoline,3-hydroxymethyl-1,2,3,4tetrahydroisoquinoline or3-methoxymethyl-1,2,3,4-tetrahydroisoquinoline.

The invention also provides compounds of formula IIB:

wherein

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4- or5-pyrimidinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy, with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl;

Z is a group of the formula

where

R₄ is hydrogen, C₁-C₆ alkyl, or (C₁-C₆ )alkyl-W-R₈, where W is O, NH, orN(C₁-C₆) alkyl, and R₈, is hydrogen or C₁-C₆ alkyl;

m is 0, 1 or2;

n is 0, 1 or 2; and

E represents CHR₅ where R₅ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, halogen, trifluoromethyl, phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds;

or

E is a group of the formula

where

R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, or a saturated5- or 6-membered ring or a partially unsaturated ring having one or twodouble bonds; or

Z is —NR₆R₇

where R₆ and R₇ are the same or different and represent

hydrogen, C₁-C₆ alkyl, (C₁-C₆ )alkyl-Y-R₉, wherein Y is O, S NH, N(C₁-C₆alkyl), and R₉ is hydrogen or C₁-C₆ alkyl; or

aryl(C₁-C₆)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4pyridinyl, 2- or 3-thienyl or 2-, 4, or 5- pyrimidinyl, each of which ismono- or disubstituted with halogen, hydroxy, (C₁-C₆ )alkyl,(C₁-C₆)alkoxy; or

R₆ and R₇ taken together represent —(CH₂)_(n)—Y—(CH₂)_(m)— wherein n is2, or 3, Y is CH₂, O, S or NR₆, wherein R₆ is C₁-C₆ alkyl, phenyl, 2-,3-, or 4pyridinyl, 2- or 3-thienyl, or 2-, 4, or 5-pyrimidinyl, and m is1, 2 or 3.

Preferred compounds of formula IIB are those where Z is 1,2,3,4tetrahydroisoquinoline, 3-hydroxyinethyl-1,2,3,4tetrahydroisoquinolineor 3-methoxymethyl-1,2,3,4tetrahydroisoquinoline.

The invention provides compounds of formula III

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4pyridinyl, 4 or5-pyriridinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy, with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl or C₁-C₆ alkenyl;

R₄ is hydrogen, C₁-C₆ alkyl, or (C₁-C₆ )alkyl-W-R₈, where W is O, NH, orN(C₁-C₆) alkyl, and R₈ is hydrogen or C₁-C₆ alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2; and

E represents CHR₅ where R₅ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, halogen, trifluoromethyl, phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds; or

E is a group of the formula

where

R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, or a saturated5- or 6-membered ring or a partially unsaturated ring having one or twodouble bonds.

Preferred compounds of formula III are those where Ar is phenyl that ismono-, di-, or trisubstituted with halogen, hydroxy, C₁-C₆ alkyl, orC₁-C₆ alkoxy, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. More preferred compounds of Formula III are those where R₁and R₂ are independently hydrogen or lower alkyl, most preferablyhydrogen or C₁-C₃ alkyl; and Ar is phenyl that is trisubstituted withC₁-C₆ alkyl, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. Most preferred compounds of Formula III are those where R₁and R₂ are independently C₁-C₃ alkyl; and Ar is phenyl that istrisubstituted in the 1, 3, and 5 positions (para and both orthopositions relative to the point of attachment to the pyrazole ring) withC₁-C₃ alkyl, most preferably methyl.

The invention provides compounds of formula IV

wherein

A is carbonyl or methylene;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl 4 or5-pyrimidinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆, alkyl, or C₁-C₆ alkoxy, with the proviso thatat least one of the positions on Ar ortho to the point of attachment tothe pyrazole ring is substituted;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl; and

R′ is hydrogen, hydroxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkyl.

Preferred compounds of formula IV are those where Ar is phenyl that ismono-, di-, or trisubstituted with halogen, hydroxy, C₁-C₆ alkyl, orC₁-C₆ alkoxy, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. More preferred compounds of Formula IV are those where R₁and R₂ are independently hydrogen or lower alkyl, most preferablyhydrogen or C₁-C₃ alkyl; and Ar is phenyl that is trisubstituted withC₁-C₆ alkyl, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. Most preferred compounds of Formula IV are those where R′is represents hydrogen, methoxymethyl, or hydroxymethyl, R₁ and R₂ areindependently C₁-C₃ alkyl; and Ar is phenyl that is trisubstituted inthe 1, 3, and 5 positions (i.e., the para and both ortho positionsrelative to the point of attachment to the pyrazole ring) with C₁-C₃alkyl, most preferably methyl.

Other preferred hydroxy alkyl or alkoxy alkyl groups at R′ in Formula IVare hydroxymethyl and methoxymethyl. Preferred compounds of formula IVare those where Z is 1,2,3,4tetrahydroisoquinoline,3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline or 3-methoxymethyl-1,2,3,4-tetrahydroiso-quinoline.

The invention further provides compounds of formula V

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4- or5-pyrimidinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy, with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted;

R₁ is hydrogen, C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl;

G is CH or N; and

R″ represents C₁-C₆ alkyl or a phenyl group optionally substituted withC₁-C₆ alkyl,

C₁-C₆ alkoxy, hydroxy, halogen, trifluoromethyl, or phenyl.

Preferred compounds of formula V are those where G is nitrogen, Ar isphenyl that is mono-, di-, or trisubstituted with halogen, hydroxy,C₁-C₆ alkyl, or C₁-C₆ alkoxy, with the proviso that at least one of thepositions on the phenyl group ortho to the point of attachment to thepyrazole ring is substituted. More preferred compounds of Formula V arethose where G is nitrogen, R₁ and R₂ are independently hydrogen or loweralkyl, most preferably hydrogen or C₁-C₃ alkyl; and Ar is phenyl that istrisubstituted with C₁-C₆ alkyl, with the proviso that at least one ofthe positions on the phenyl group ortho to the point of attachment tothe pyrazole ring is substituted. Most preferred compounds of Formula Vare those where G is nitrogen, R″ is methyl or phenyl, R₁ and R₂ areindependently C₁-C₃ alkyl; and Ar is phenyl that is trisubstituted inthe 1, 3, and 5 positions (para and both ortho positions relative to thepoint of attachment to the pyrazole ring) with C₁-C₃, alkyl, mostpreferably methyl. Other most preferred compounds of Formula V are thosewhere A is methylene and G is nitrogen, R″ is methyl or phenyl, R₁ andR₂ are independently C₁-C₃ alkyl; and Ar is phenyl that istrisubstituted in the 1, 3, and 5 positions (para and both orthopositions relative to the point of attachment to the pyrazole ring) withC₁-C₃ alkyl, most preferably methyl.

The invention provides compounds of formula VI

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4 or5-pyrimidinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy, with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted;

R₁ is hydrogen, or C₁-C₆ alkyl;

R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl;

R_(a) represents hydrogen or C₁-C₆ alkyl; and

R_(b) represents C₁-C₆ alkyl or a phenyl group optionally substitutedwith C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, or trifluoromethyl.

Preferred compounds of formula VI are those where Ar is phenyl that ismono-, di-, or trisubstituted with halogen, hydroxy, C₁-C₆ alkyl, orC₁-C₆ alkoxy, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. More preferred compounds of Formula VI are those where R₁and R₂ are independently hydrogen or lower alkyl, most preferablyhydrogen or C₁-C₃ alkyl; and Ar is phenyl that is trisubstituted withC₁-C₆ alkyl, with the proviso that at least one of the positions on thephenyl group ortho to the point of attachment to the pyrazole ring issubstituted. Most preferred compounds of Formula V are those where R_(a)is hydrogen or lower alkyl, most preferably methyl, R_(b) is optionallysubstituted phenyl, R₁ and R₂ are independently C₁-C₃ alkyl; and Ar isphenyl that is trisubstituted in the 1, 3, and 5 positions (para andboth ortho positions relative to the point of attachment to the pyrazolering) with C₁-C₃ alkyl, most preferably methyl.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where n is 0-4, and thelike. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

When a compound of formula I is obtained as a mixture of enantiomersthese may be separated by conventional methods such as crystallizationin the presence of a resolving agent, or chromatography, for example,using a chiral HPLC column.

By the terms (C₁-C₆)alkyl and lower alkyl is meant straight and branchedchain alkyl groups having from 1-6 carbon atoms as well as cyclic alkylgroups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl.Specific examples of such alkyl groups are methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl andn-pentyl. Preferred C₁-C₆ alkyl groups are methyl, ethyl, propyl, butylor cyclopropylmethyl.

By the terms (C₁-C₆)alkoxy and lower alkoxy is meant straight andbranched chain alkoxy groups having from 1-6 carbon atoms.

By hydroxy C₁-C₆ alkyl is meant a C₁-C₆ alkyl group carrying a terminalhydroxy moiety.

By C₁-C₆ alkoxy C₁-C₆ alkyl is meant a group of the formula—(CH₂)_(x)O(CH₂)_(y)CH₃, where x and y independently represent integersof from 1-6.

By the term C₁-C₆ alkenyl is meant straight or branched chainhydrocarbon groups having from 1-6 carbon atoms and at least one doublebond.

By halogen, halo, or halide is meant fluorine, chlorine, bromine andiodine substituents.

By aryl(C₁-C₆)alkyl is meant aryl groups attached to the parent group bya straight or branched chain alkyl group having 1-6 carbon atoms. Thearyl groups include phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4-, or 5- pyrimidinyl and are optionally substitutedwith up to two groups selected from halogen, hydroxy, (C₁-C₆)alkyl, and(C₁-C₆)alkoxy.

Representative examples of-pyrazoles according to the invention areshown in Table I below.

TABLE 1 Compound No. 1

2

3

11

12

15

16

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for CRF receptor activity.

Assay for CRF Receptor Binding Activity

CRF receptor binding was performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Biochemical, Pharmacological, andAutoradiographic Methods to Study Corticotropin-Releasing FactorReceptors. Methods in Neurosciences, Vol. 5, 1991). Membrane pelletscontaining CRF receptors were resuspended in 50 mM Tris buffer pH 7.7containing 10 mM MgCl₂ and 2 mM EDTA and centrifuged for 10 minutes at48000 g. Membranes were washed again and brought to a finalconcentration of 1500 mg/ml in binding buffer (Tris buffer above with0.1% BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For the bindingassay, 100 ml of the membrane preparation was added to 96 well microtubeplates containing 100 ml of 1251-CRF (SA 2200 Ci/mmol, finalconcentration of 100 pM) and 50 ml of drug. Binding was carried out atroom temperature for 2 hours. Plates were then harvested on a Brandel 96well cell harvester and filters were counted for gamma emissions on aWallac 1205 Betaplate liquid scintillation counter. Non specific bindingwas defined by 1 mM cold CRF. IC₅₀ values were calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.). The binding affinity for the compounds of formula Iexpressed as IC50 value, generally range from about 0.5 nanomolar (nM)to about 10 micromolar (μM).

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

A representative illustration of methods suitable for the preparation ofcompounds of the present invention is shown in Scheme I. Those havingskill in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present invention.

wherein

Ar, R₁, R₂, and Z are as defined as above for Formula I; and

X is a leaving group, such as, for example, chloride or bromide.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE 1 A. Ethel 3-ethyl-2,4-dioxo-4-(2,4,6-trimethylphenyl)butanoate

Sodium (1.0 g, 42.1 mmol, spheres) was cautiously added to 25 mL ofabsolute EtOH with stirring. After the sodium had dissolved, diethyloxalate (6.0 g, 42.1 mmol) was added dropwise to the resulting solutionat 0° C., followed by addition of a solution of 2′, 4′,6′-trimethylbutyrophenone (8 g, 42.1 mmol) in 5 mL of absolute EtOH. Thereaction mixture was slowly warmed to 50 ° C. and stirred overnight. Thesolvent was then evaporated. The resulting residue was washed withhexane, diluted with water, acidified with 1 N HCl, and then extractedwith ether. The extacts were washed with brine, dried over Na₂SO₄ andconcentrated to give 6.5 g of an oil which was used in the next reactionwithout further purification.

B. Ethyl 4-ethyl-3-2,4,6-trimethylphenyl)-1H-pyrrole-5-carboxylate

A mixture of ethyl 3-ethyl-2,4-dioxo4(2,4,6trimethylphenyl)butanoate(6.0 g, 20.7 mmol) and hydrazine dihydrochloride (2.17 g, 20.7 mmoL) in100 mL of EtOH was stirred at 80° C. for 6 hours. The solvent was thenremoved from the mixture. 200 mL of water was added to the residue andmixture was neutralized by the addition of solid NaHCO₃. The product wasextracted into ether. The ether extract was dried over Na₂SO₄ andevaporated to give 5.8 g as an oil which was used in the next reactionwithout further purification.

C. Ethyl 1,4-diethyl-3-(2,4,6-trimethylphenyl-1H-Myrazole-5-carboxylate

To a red mixture of the product of step B (1.0 g, 3.5 mmol) and powderedKOH (2.0 g) in 50 mL of DMSO was added bromoethane (2.0 mL) at 60° C.The reaction mixture was stirred for I hour then poured into ice-water.The resulting mixture was extracted with ether. The ether extract waswashed with brine, dried over Na2SO₄, and concentrated to provide an oilwhich was comprised of the isomeric pair ethyl1,4-diethyl-3-2,4,6-trimethylphenyl)-pyrazole-5-carboxylate and ethyl1,4-diethyl-5-(2,4,6-trimethylphenyl)-pyrazole-3- carboxylate in a 1:1mixture. The isomers were separated by column chromatography over silicagel using CH₂Cl₂ as eluent. The faster moving fraction, comprising thetitled compound, was collected. Evaporation of the solvent gave about400 mg of the desired compound as an oil. ¹H NMR (CDCl₃): 0.95 (t, 3H),1.42 (mn, 6H) 2.00 (s, 6H), 2.30 (s, 3H), 2.42 (q, 2H), 4.40 (q, 2H),4.59 (q, 2H), 6.90 (s, 2H) ppm.

D. 5-Chloromethyl-1,4diethyl-3-(2,4,6-tiethylphenyl)-1H-Dyrazolehydrochloride

To a solution of the product of step C (320 mg, 1 mmol) in 10 mL ofanhydrous THF was added dropwise a solution of LiAiH4 (3 mL, 1 M in THF)at 0° C. After stirring for 2 hours, water was cautiously added. Themixture was then extracted repeatedly with ether. The combined extractswere washed with brine, dried and concentrated. The residue wasdissolved in 1 mL of SOCl₂, stirred at 60° C. for 2 hours and evaporatedto provide the title compound which was used in the next reactionwithout further purification.

E.2-{1-[1,4-Diethyl-3-(2,4,6-trimethylphenyl-1H-pyrazolyl-5-yl]methyl}-1,2,3,4tetahydroisoquinoline(Compound 1)

A mixture of the product of step D (from above) and1,2,3,4tetrahydroisoquinoline (150 mg, 1.1 mmol) and triethylamine (1mL) in 5 mL of DMF was heated at 100° C. for 1 hour. The mixture wascooled, diluted with water, basified with 1 N NaOH, and finallyextracted with ether. The organic layer was separated, washed withbrine, dried over Na₂SO₄ and concentrated to give about 500 mg of thecrude compound as an oil. The oil was purified through silica gel columnchromatography to give 160 mg of the title compound as an oil. ¹H NMR(CDCl₃): 0.90 (t, 3H), 1.39 (t, 3H), 2.05 (s, 6H), 2.25 (q, 2H), 2.31(s, 3H), 2.76 (q, 2H), 2.90 (q, 2H), 3.66 (s, 2H), 3.68 (s, 2H), 4.24(q, 2H), 6.90 (s, 2H), 7.05 (m, 1H), 7.15 (m, 3H)ppm.

The following compounds are prepared essentially according to proceduresset forth above in Example 1.

EXAMPLE 22-{1-[1,4-Diethyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline(Compound 2) EXAMPLE 3 2-{1-[1,4-Diethyl-3-(2,4,6-trimethylpheny1)1H-pyrazol-5-yl]-methyl}-3-methoxymethyl-1,2,3,4-tetrahydroisoquinoline(Compound 3) EXAMPLE 42-{1-[1-Ethyl-4-methyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-1,2,3,4-tetrahydroisoquinolineEXAMPLE 5 2-{1-[1-Ethyl-4-methyl-3-(2,4,6-trimethylphenyl)1H-pyrazol-5-yl]-methyl}-3-hydroxymethyl- 1,2,3,4-tetrahydroisoquinoline EXAMPLE 62-{1-[1-Ethyl-4-methyl-3-(2,4,trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-3-methoxymethyl- 1,2,3,4-tetrahydroisoquinoline EXAMPLE 7 1-{1-[1-Ethyl-4-methyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-2-hydroxymethyl-piperidineEXAMPLE 82-{1-[4-Methyl-1-propyl-3-2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-1,2,3,4-tetrahydroisoquinolineEXAMPLE 92-{1-[4-Methyl-1-propyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinolineEXAMPLE 102-{1-[4-Methyl-1-propyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-3-methoxymethyl-1,2,3,4-tetrahydroisoquinolineEXAMPLE 112-{[1,4-diethyl-3-(2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolineEXAMPLE 12N-Ethyl-N-phenylmethyl-1,4-diethyl-3-(2,4,6-trimethylphenyl)-1H-pyrazole-5-carboxamideEXAMPLE 13N-Cyclopropylmethyl-N-propyl-1,4diethyl-3-2,4,6-trimethylphenyl)-1H-pyrazole-5-carboxamideEXAMPLE 14N,N-(2,2-Dimethoxyethyl)1,4-diethyl-3-2,4,6trimethylphenyl)-1H-pyrazole-5-carboxamideEXAMPLE 151-{1-[1-Ethyl-4-methyl-3-2,4,6trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-methyl-piperazineEXAMPLE 161-{1-[1-Ethyl4-methyl-3-2,4,6trimethylphenyl)-1H-pyrazol-5-yl]-methyl}phenyl-piperazineEXAMPLE 171-{1-[1-Ethyl-4-methyl-3-2,4,6-trimethylphenyl)-1H-pyrazol-5-yl]-methyl}-morpholine

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein Ar is phenyl, 1-or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or5-pyrimidinyl, each of which is mono-, di-, or trisubstituted withhalogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy with the proviso that atleast one of the positions on Ar ortho to the point of attachment to thepyrazole ring is substituted; R₁ is hydrogen or C₁-C₆ alkyl; R₂ ishydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl; Z is a group of the formula

where R₄ is hydrogen, C₁-C₆ alkyl, or (C₁-C₆) alkyl-W-R₈, where W is O,S, NH, or N(C₁-C₆)alkyl, and R₈ is hydrogen or C₁-C₆ alkyl; m is 0, 1 or2; n is 0, 1 or 2; and E represents CHR₅ where R₅ is hydrogen, C₁-C₆alkyl, C₁-C₆ alkoxy, hydroxy, halogen, or trifluoromethyl, phenyl,naphthyl, pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl,pyrazolyl, pyrazinyl, or a saturated 5- or 6- membered ring or apartially unsaturated ring having one or two double bonds; or E is agroup of the formula

where R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and the B ring is phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds; or Z is —NR₆R₇ where R₆ and R₇ are the same ordifferent and represent hydrogen, C₁-C₆ alkyl, (C₁-C₆)alkyl-Y-R₉,wherein Y is O, S, NH, N(C₁-C₆ alkyl), and R₉ is hydrogen or C₁-C₆alkyl; or aryl(C₁-C₆)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl,2-, 3-, or 4 pyridinyl, 2- or 3-thienyl or 2-, 4, or 5- pyrimidinyl,each of which is mono- or disubstituted with halogen, hydroxy,(C₁-C₆)alkyl, (C₁-C₆) alkoxy; or R₆ and R₇ taken together represent——(CH₂)_(n)—Y—(CH₂)_(m)—wherein n is 2, or 3, Y is CH₂, O, S or NR_(6,)wherein R₆, is C₁-C₆ alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, and m is 1, 2 or
 3. 2. Acompound or salt according to claim 1, wherein Z is1,2,3,4-tetrahydroisoquinoline, 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, or 3-methoxymethyl-1,2,3,4-tetrahydroisoquinoline.
 3. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein: A is methylene orcarbonyl; Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or3thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, ortri-substituted with halogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy withthe proviso that at least one of the positions on Ar ortho to the pointof attachment to the pyrazole ring is substituted; R₁ is hydrogen orC₁-C₆ alkyl; R₂ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkenyl; R₄ ishydrogen, C₁-C₆ alkyl, or (C₁-C₆ ) alkyl-W-R₈, where W is O, S, NH, orN(C₁-C₆) alkyl, and R₈ is hydrogen or C₁-C₆ alkyl; m is 0, 1 or 2; n is0, 1 or 2; and E represents CHR₅ where R₅ is hydrogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, halogen, or trifluoromethyl, phenyl, naphthyl,pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl,pyrazinyl, or a saturated 5- or 6- membered ring or a partiallyunsaturated ring having one or two double bonds; or E is a group of theformula

where R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, halogen, ortrifluoromethyl; and the B ring is phenyl, naphthyl, pyridinyl,pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or asaturated 5- or 6- membered ring or a partially unsaturated ring havingone or two double bonds.
 4. A compound or salt according to claim 3wherein Ar is phenyl that is mono-, di-, or trisubstituted with halogen,hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy.
 5. A compound or salt accordingto claim 3 wherein R₁ and R₂ are independently hydrogen or C₁-C₃ alkyl;and Ar is phenyl that is tri-substituted with C₁-C₆ alkyl.
 6. A compoundaccording to claim 3, wherein: R₁ and R₂ are independently C₁-C₃ alkyl;and Ar is phenyl that is substituted in the 1, 3, and 5 positions withC₁-C₃ alkyl.
 7. A compound according to claim 3, wherein R₁ and R₂ areindependently C₁-C₃ alkyl; and Ar is phenyl that is substituted in the1, 3, and 5 positions with methyl.
 8. A pharmaceutical compositioncomprising a compound according to claim 1 together with at least onepharmaceutically acceptable carrier.
 9. A pharmaceutical compositioncomprising a compound according to claim 3 together with at least onepharmaceutically acceptable carrier.
 10. A method for treating stressrelated disorders comprising administering to a patient in need of suchtreatment and effective amount of a compound according to claim
 1. 11. Amethod according to claim 10, wherein the disorder is post traumaticstress disorder.
 12. A method for treating stress related disorderscomprising administering to a patient in need of such treatment andeffective amount of a compound according to claim
 3. 13. A methodaccording to claim 12 wherein the disorder is post traumatic stressdisorder.
 14. A method for treating anxiety comprising administering toa patient in need of such treatment and effective amount of a compoundaccording to claim
 1. 15. A method for treating anxiety comprisingadministering to a patient in need of such treatment and effectiveamount of a compound according to claim
 3. 16. A method for treatingdepression comprising administering to a patient in need of suchtreatment and effective amount of a compound according to claim
 1. 17. Amethod for treating depression comprising administering to a patient inneed of such treatment and effective amount of a compound according toclaim 3.